1. Field of the Invention
The present invention relates to the field of medical therapeutics and more specifically relates to the field of glaucoma and ocular hypertension therapy utilizing novel instruments and techniques for opto-thermal mediation of a patient's trabecular meshwork for enhancing the mitotic rate of endothelial meshwork cells and for reduction of biostructural laxity within the meshwork, which meshwork biocharacteristics may be subject to cell-division inhibitions and/or other degradations.
2. Description of the Related Art
Glaucomas comprise a group of debilitating eye diseases that are the leading cause of blindness in the United States and around the world. The pathophysiological mechanisms of glaucomas are not fully understood. The principal sign of the disease is elevated intraocular pressure (IOP). Such elevations of IOP ultimately can cause damage to the optic nerve head and result in impairment to, or loss of, normal visual function. It is known that elevated IOP is caused by an excess of fluid or aqueous AQ within the eye, which is continually produced by the ciliary body CB and drained through the trabecular meshwork M to leave the eye or globe 5 (see FIGS. 1A-1D). The excess intraocular fluid generally results from blockage or impairment of the normal drainage from the anterior chamber AC via the trabecular meshwork M. The meshwork consists of about 10 to 25 layers of perforated trabecular plates (TP.sub.1. . . TP.sub.r) or sheets around the filtration angle FA of the anterior chamber AC, having a width of about 1,000 .mu.m to 1,500 .mu.m (1.0 mm. to 1.5 mm.) in a circumference ranging from 35,000 to 40,000 .mu.m. FIGS. 1A-1B show electron micrographs of trabecular plates TP with FIG. 1B including a representation of an endothelial cell layer EC of trabecular beam B with the beam core BC believed to be predominantly collagen and GAGs (glucosaminoglycans) or ground substance. FIG. 1C illustrates that each successively deeper plate (more anterior plate) of the meshwork M has smaller perforations PF or openings between the beams B than more exposed (posterior) trabecular plates. Further, the intraplate spacing IPS diminishes with the successively deeper plates (FIG. 1C). The meshwork M thus serves as a filtration mechanism wherein cellular detritus, etc. in the aqueous outflow is captured before it passes into Schlemm's canal SCH where the aqueous is transported away form the eye (FIG. 1D). The meshwork M lies about 750 .mu.m to 950 .mu.m beneath the anterior surface of the sclera SC.
A number of ophthalmic disease conditions are related to the trabecular meshwork and can be linked to distinct processes or pathological conditions within a patient's eye. Any disease of the trabecular meshwork shares the characteristic of elevating IOP. Chandler et al. described many forms of glaucoma, the principal ones being: primary open-angle glaucoma (POAG); progressive low-tension glaucoma; pigment dispersion and pigmentary glaucoma; angle-closure glaucoma; combined open-angle and angle-closure glaucoma, exfoliation and open-angle glaucoma; angle-closure glaucoma due to multiple system cysts of iris and ciliary body; angle-closure glaucoma secondary to occlusion of the central retina vein; angle-closure glaucoma secondary to bilateral transitory myopia; ghost-cell glaucoma; lens-induced glaucoma; glaucoma due to intraocular inflammation; neovascular glaucoma; glaucoma associated with extraocular venous congestion; essential atrophy of the iris with glaucoma. among others. (Chandler, et. al., Glaucoma, 3rd Ed., Lea & Febliger; Phila. (1986)) In all of the above-listed glaucoma syndromes, elevated IOP results from an increase in resistance to aqueous humor outflows through the trabecular meshwork.
In terms of incidence, primary open-angle glaucoma (POAG) is the most prevalent form of the disease affecting up to 0.5% of the population between ages of 35 to 75. The incidence of glaucoma rises with age to over 6% of the population 75 years are older. One identifiable component of the POAG syndrome is the loss of endothelial cells within the meshwork which is associated with a degeneration of the normal trabecular biostructure. It is known that the human aging process itself leads to a progressive loss of trabecular endothelial cells EC which compromises normal aqueous outflows therethrough. When examined in tissue cultures, degraded endothelial tissue from POAG patients appears similar to that of "aging" individuals.
Other characteristics believed common to POAG (as well as many other glaucomas listed above) relate to a biostructural obstructive syndrome of the trabecular plates TP, for example, resulting from compression of the plates into a matt-like form that reduces intraplate spacing IPS (FIG. 1C). This factor reduces the capacity of the meshwork to act as a filtering mechanism and may develop after the meshwork is clogged with cellular detritus, pigments, etc. Such an obstructive syndrome, it is believed, also is characterized by increased laxity of the trabecular beams B allowing their collapse which thus reduces intraplate spacing. The most likely causes of the meshwork degradations described above may be cumulative stresses from various factors (e.g., oxidative, phagocytic, glucocorticoidal stresses). The fact that increased outflow resistance appears in the non-glaucoma "aging" population further suggests that both trabecular endothelial cellular processes and an obstructive meshwork syndrome play significant roles in decreasing aqueous outflows.
The normal IOP for humans usually ranges from about 10 to 22 mm. Hg. (1.3-2.7 kilopascals) and is maintained by a balance in the aqueous production by the ciliary body CB, inflows to the anterior chamber AC and outflows therefrom. As described above, in a normal eye, the aqueous drains from the anterior chamber through the meshwork into Schlemm's canal SCH, through which it leaves the eye. In patients in a glaucomous state, besides passing through Schlemm's canal, the aqueous may also pass through the ciliary muscle CM into the suprachoroidal space and finally leave the eye through the sclera SC (FIG. 1D).
For purposes of description, the intraocular pressure (IOP) in a human can be defined by a formula of the following type: EQU IOP=P.sub.e +(F.sub.t -F.sub.uv).times.R:(TM.sub.cep, TM.sub.sp, TM.sub.br)
where P.sub.e is the episcleral venous pressure (generally regarded as being around 9 mm. Hg.); F.sub.t is the total outflow of the aqueous humor from the anterior chamber, F.sub.uv is the fraction of aqueous passing by the uveoscleral route; R is the resistance to outflow of aqueous through the trabecular meshwork into Schlemm's canal, which can be considered to be functionally related to (i) the vitality of trabecular endothelial cellular cellular and enzymatic processes (TM.sub.cep), (ii) the dimensions of intraplate spacing between (TM.sub.ips) relative to a norm, and (iii) the trabecular beam resiliency (T.sub.br) or biostructural tension within the meshwork under the pressure of aqueous outflow therethrough. Such a formula is useful for understanding the targets of various prior art therapies, if not for use as an actual mathematical model.
Among several therapies targeted at various elements of the above equation, two forms of treatment are common: (i) medical or drug therapies, and (ii) trans-corneal laser irradiation of the trabecular meshwork via a goniolens (see FIG. 2A). In medication therapies, the objective may be to lower IOP by either of several routes: reducing the aqueous flow total (F.sub.t in the above equation); increasing uveoscieral flow (F.sub.uv in above equation); or altering resistance to outflow (R), by stimulating endothelial cellular processes (TM.sub.cep) which is believed to act on outflow resistance. Drug therapies have the disadvantages of requiring a lifelong treatment; causing significant side effects; being very costly (between $1,000-$2,000/yr.); and being unavailable or unaffordable in lesser developed countries of the world where the incidence of glaucoma is highest.
In the laser therapies, ALT (argon laser trabeculoplasty) and SLT (selective laser trabeculoplasty) have been developed which both rely on a trans-corneal approach to the posterior surface of the meshwork. Introduced in the 1980's, ALT uses an argon laser operating at a wavelength (.lambda.) of 488 nm to 514.5 nm with a long pulse duration of about 0.10 second and a power range of from 500-1000 mW to irradiate a series of about 50 spots only around the 180.degree. of the meshwork (see FIG. 2A). In ALT, the ophthalmologist utilizes a goniolens to direct laser beam strikes on the exposed surface of the trabecular plates TP. The causative mechanisms of ALT have never been clearly understood. It has been proposed that each ALT beam's incidence on the meshwork causes a burn or a melt and results in the formation of scar tissue that contracts (or tensions) a portion of the meshwork around the burn (cf. TM.sub.br or resiliency of beam B in above formula). According to another view, the ALT meshwork burns cause a wound healing response resulting in significant cell division and the transient repopulation of endothelial meshwork cells, at least in zones around the burns (cf. TM.sub.cep above). FIG. 2B shows an electron micrograph of an ALT meshwork burn indicated at 6, which may tension the meshwork at the burn periphery indicated at 7. A principal disadvantage of ALT is that it can only be performed twice on an eye--once in the superior (or nasal) 180 degrees of the meshwork and once in the inferior (or temporal) 180 degrees. The laser melts are too significant to repeat the treatment in the same portion of the meshwork.
The more recently developed trans-corneal laser approach is SLT, which uses a short-pulse, frequency-doubled, 530 nm Nd:YAG laser with pulse duration of 3 nanoseconds and energy levels that range from 0.60 mJ to 1.20 mJ. The SLT modality is called "selective photothermolysis" by its inventor (Dr. M. Latina) wherein the proposed wavelength is absorbed by endogenous pigment within the meshwork which kills (or lyses) the pigmented cells without damaging the non-pigmented cells (see U.S. Pat. No. 5,549,596). In theory, the short pulses allow heat to dissipate from the absorbing pigmented cells before killing adjacent cells (see FIG. 3). The SLT inventor proposes that the causative mechanisms of increasing aqueous outflows relate to (i) an inflammatory response in the meshwork that results in activation of enzyme systems that clean up the meshwork, and (ii) a mild expansion of the meshwork plates or perforations by killing pigmented cells with a photothermal or microcavitation effect (FIG. 3). The following table compares the ALT and SLT parameters.
Pulse Treatment .lambda. Duration Power Beam Size Area ALT 488-514.5 0.1 500-1000 mW 50 50 spots/ nm second .mu.m 180.degree. SLT 530 3 0.6-1.2 mJ 300-400 50 spots/ nm nanoseconds .mu.m 180.degree.
Several disadvantages are associated with the ALT/SLT modalities. First, both systems approach the meshwork through the anterior chamber AC by means of a goniolens. For this reason, the wavelengths must be selected from a portion of the spectrum that penetrates through the cornea C and aqueous AQ without the light energy being absorbed and extinguished--a distance of about 4 mm. to 8 mm. (4000 .mu.m to 8000 .mu.m). This factor greatly limits the choice of possible wavelengths--each of which has a different absorption coefficient in water (see FIG. 4A). The requirement of using a goniolens along with a laser aiming beam also makes the ALT/SLT approach technique dependent--making the therapy available only to highly skilled surgeons.
A second disadvantage the ALT/SLT modalities relates to the lack of exact understandings of the causative mechanisms for improving outflow facility. Since ALT has effects that last for about 5 years at most--and can be repeated only once--the medical and surgical communities have not developed a consensus about sequencing medical and surgical therapies. Glaucoma is a disease state that requires lifelong management. Some physicians propose that ALT be resorted to only after drug therapies have lost their effectiveness; other physicians propose ALT as a first line of defense in order to delay a lifetime of drug therapy and the attendant side effects.
Other significant disadvantages of ALT/SLT relate to the fact that both deliver similar photothermal effects to a limited depth within the trabecular plate structure. That is, the ALT/SLT causative mechanisms--no matter what they are--probably only operate within the trabecular plates TP most exposed to the incident beam which thus absorb the beam's photonic energy. This factor suggests that only the first few plates (most posterior plates) exposed to the anterior chamber AC are affected by such energy delivery--perhaps only about 10%-20% of the larger dimensioned trabecular plates. It is postulated that the underlying (anterior) trabecular plates that have smallest dimensioned perforations PF and the least intraplate spacing IPS are degraded to the greatest degree and thus play the most significant role in increasing IOP by clogging the pathways to Schlemm's canal (see FIG. 1D). Yet, these most anterior meshwork regions probably remain untreated by ALT and SLT.
Further, studies have shown that ALT is not effective in all patients, and actually increases IOP in over 20% of patients. Additionally, in recent SLT patients, the following complications have been documented: uveitis in the form of iritis in virtually all treated eyes; corneal burns in up to 25% of treated eyes; and anterior synechiae or adhesions due to the significant absorption of light energy in the pigmented cells of the meshwork.
What is needed is an improved technique for effecting biostructural changes in the trabecular meshwork to facilitate aqueous outflows that provides: (i) means for stimulating endothelial cell division to cause cell repopulation and rejuvenation within the trabecular plate structure; (ii) means for inducing a slight inflammatory or wound healing response to activate enzymatic systems such as stromolysin and metalloproteases that may help clean up the meshwork; (iii) means for causing the desired biostimulative effects without photocoagulation, photodisruption or photothermolysis of endothelial layers of the meshwork as in ALT/SLT; (iv) MIS (minimally invasive surgical) means for causing the desired effects in a repeatable maintenance therapy that can continue over the lifetime of the glaucoma patient; (v) MIS means for meshwork treatment that can be evaluated in all patients before resorting to drug therapies; (vi) MIS means for treating 360.degree. of the meshwork instead of 180.degree. or less; (vii) means for causing the desired effects substantially equally on all trabecular plates from the most posterior to the most anterior; (viii) MIS means simultaneous treatment of a substantial arc of the meshwork with a device in a single treatment position rather than time-consuming treatment in a series of spots; (ix) MIS means for biostimulating the trabecular structure in the many forms of glaucoma (other than POAG) that are not possible with a goniolens and laser strikes through the anterior chamber, (x) MIS means for treating the meshwork without risk of any corneal bums; and (xi) MIS means for treating the trabecular structure that is not technique-dependent and capable of being performed by optometrists or other lesser-skilled health care professionals in the lesser developed countries of the world.